Origins of Chevron Rollovers in Non-Two-State Protein Folding Kinetics

Chevron rollovers of some proteins imply that their logarithmic folding rates are nonlinear in native stability. This is predicted by lattice and continuum G\=o models to arise from diminished accessibilities of the ground state from transiently populated compact conformations under strongly native conditions. Despite these models' native-centric interactions, the slowdown is due partly to kinetic trapping caused by some of the folding intermediates' nonnative topologies. Notably, simple two-state folding kinetics of small single-domain proteins are not reproduced by common G\=o-like schemes.Comment: 10 pages, 4 Postscript figures (will appear on PRL

Automated entire thrombus density measurements for robust and comprehensive thrombus characterization in patients with acute ischemic stroke

Background and Purpose: In acute ischemic stroke (AIS) management, CT-based thrombus density has been associated with treatment success. However, currently used thrombus measurements are prone to inter-observer variability and oversimplify the heterogeneous thrombus composition. Our aim was first to introduce an automated method to assess the entire thrombus density and then to compare the measured entire thrombus density with respect to current standard manual measurements. Materials and Method: In 135 AIS patients, the density distribution of the entire thrombus was determined. Density distributions were described usingmedians, interquartile ranges (IQR), kurtosis, and skewedness. Differences between themedian of entire thrombusmeasurements and commonly applied manualmeasurements using 3 regions of interest were determined using linear regression. Results: Density distributions varied considerably with medians ranging from 20.0 to 62.8 HU and IQRs ranging from 9.3 to 55.8 HU. The average median of the thrombus density distributions (43.5 ± 10.2 HU) was lower than the manual assessment (49.6 ± 8.0 HU) (p<0.05). The difference between manual measurements and median density of entire thrombus decreased with increasing density (r = 0.64; p<0.05), revealing relatively higher manual measurements for low density thrombi such that manual density measurement tend overestimates the real thrombus density. Conclusions: Automatic measurements of the full thrombus expose a wide variety of thrombi density distribution, which is not grasped with currently used manual measurement. Furthermore, d

Two-year clinical follow-up of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in The Netherlands (MR CLEAN): Design and statistical analysis plan of the extended follow-up study

Background: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up. Methods: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up. Discussion: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness. Trial registration:NTR1804. Registered on 7 May 2009; ISRCTN10888758. Registered on 24 July 2012 (main MR CLEAN trial); NTR5073. Registered on 26 February 2015 (extended follow-up study)

Phenophase-based comparison of field observations to satellite-based actual evaporation estimates of a natural woodland: miombo woodland, southern Africa

The trend and magnitude of actual evaporationacross the phenophases of miombo woodlands are unknown.This is because estimating evaporation in African woodlandecosystems continues to be a challenge, as flux observationtowers are scant if not completely lacking in most ecosystems.Furthermore, significant phenophase-based discrepanciesin both trend and magnitude exist among the satellitebasedevaporation estimates (i.e. Global Land EvaporationAmsterdam Model (GLEAM), moderate resolution imagingspectroradiometer (MODIS), operational simplified surfaceenergy balance (SSEBop), and water productivity throughopen-access remotely sensed derived data (WaPOR)), makingit difficult to ascertain which of the estimates are close tofield conditions. Despite the many limitations with estimationof evaporation in woodlands, the development and applicationof the distributed temperature system (DTS) is providingdeepened insights and improved accuracy in woodlandenergy partitioning for evaporation assessment. In thisstudy, the Bowen ratio distributed temperature sensing (BRDTS)approach is used to partition available energy and estimateactual evaporation across three canopy phenophasesof the miombo woodland, covering the entire 2021 dryseason (May–October) and early rain season (November–December) at a representative site in Mpika in Zambia,southern Africa. To complement the field experiment, foursatellite-based evaporation estimates are compared to thefield observations. Our results show that actual evaporationof the miombo woodland appears to follow the trend of thenet radiation, with the lowest values observed during thephenophase with the lowest net radiation in the cool dryseason and the highest values during the phenophase withpeak net radiation in the early rainy season. It appears thecontinued transpiration during the driest period in the dormantphenophase (with lowest canopy cover and photosyntheticactivities) may be influenced by the species-dependentadapted physiological attributes such as access to moisturein deep soils (i.e. due to deep rooting), plant water storage,and the simultaneous leaf fall and leaf flush among miomboplants. Of the four satellite-based evaporation estimates, onlythe WaPOR has a similar trend to the field observationsacross the three phenophases. However, all four satellitebasedestimates underestimate the actual evaporation duringthe dormant and green-up phenophases. Large coefficientsof variation in actual evaporation estimates among thesatellite-based estimates exist in the dormant and green-upphenophases and are indicative of the difficulty in estimatingactual evaporation in these phenophases. The differences betweenfield observations and satellite-based evaporation estimatescan be attributed to the model structure, processes, andinputs

Variations in canopy cover and its relationship with canopy water and temperature in the miombo woodland based on satellite data

Understanding the canopy cover relationship with canopy water content and canopy temperature in the Miombo ecosystem is important for studying the consequences of climate change. To better understand these relationships, we studied the satellite data-based land surface temperature (LST) as proxy for canopy temperature, leaf area index (LAI), and the normalized difference vegetation index (NDVI) as proxies for canopy cover. Meanwhile, the normalized difference infrared index (NDII) was used as a proxy for canopy water content. We used several statistical approaches including the correlated component regression linear model (CCR.LM) to understand the relationships. Our results showed that the most determinant factor of variations in the canopy cover was the interaction between canopy water content (i.e., NDII) and canopy temperature (i.e., LST) with coefficients of determination (R2) ranging between 0.67 and 0.96. However, the coefficients of estimates showed the canopy water content (i.e., NDII) to have had the largest percentage of the interactive effect on the variations in canopy cover regardless of the proxy used i.e., LAI or NDVI. From 2009-2018, the NDII (proxy for canopy water content) showed no significant (at alpha level 0.05) trend. However, there was a-n significant upward trend in LST (proxy for canopy temperature) with a magnitude of 0.17 °C/year. Yet, the upward trend in LST did not result in significant (at alpha level 0.05) downward changes in canopy cover (i.e., proxied by LAI and NDVI). This result augments the observed least determinant factor characterization of temperature (i.e., LST) on the variations in canopy cover as compared to the vegetation water content (i.e., NDII).Water Resource

In vivo recovery and safety of human factor VIII product AAFACT in patients with haemophilia A.

Item does not contain fulltextAAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70 previously treated haemophilia A patients were included (73% severe, 14% moderate and 13% mild haemophilia A). Most of these patients were followed during 4 years for the appearance of adverse events, possible transmissions of blood-borne viruses and the occurrence of antibodies against FVIII. The efficacy of treatment was determined in each patient by the in vivo recovery of FVIII. During this study, only six adverse events, possibly related to the use of AAFACT, were reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV and HCV in the seronegative patients have not been observed. In none of the patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during this study was not different from the in vivo recovery observed in eight patients during the preregistration study. There was a correlation of in vivo recovery with age and body weight. From these results, we conclude that the clinical usage of this human plasma-derived FVIII product is efficient and safe